Human Gene Module / Chromosome 15 / APBA2

APBA2amyloid beta (A4) precursor protein-binding, family A, member 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 8
Rare Variants / Common Variants
12 / 0
Aliases
APBA2, X11L,  MINT2,  LIN-10,  HsT16821,  MGC99508,  D15S1518E,  MGC:14091
Associated Syndromes
-
Chromosome Band
15q13.1
Associated Disorders
-
Relevance to Autism

Rare mutations in the APBA2 gene have been identified with autism (Babatz et al., 2009) as well as with schizophrenia (Kirov et al., 2008).

Molecular Function

A neuronal adapter protein essential for synaptic transmission.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to APBA2 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Mint2/X11-like colocalizes with the Alzheimer's disease amyloid precursor protein and is associated with neuritic plaques in Alzheimer's disease McLoughlin DM , et al. (1999) No -
2 Recent Recommendation Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia Kirov G , et al. (2007) No -
3 Recent Recommendation X11-like protein deficiency is associated with impaired conflict resolution in mice Sano Y , et al. (2009) No -
4 Primary Copy number and sequence variants implicate APBA2 as an autism candidate gene Babatz TD , et al. (2009) Yes -
5 Recent Recommendation Increased amyloidogenic processing of transgenic human APP in X11-like deficient mouse brain Kondo M , et al. (2010) No -
6 Support Genome-wide characteristics of de novo mutations in autism Yuen RK et al. (2016) Yes -
7 Recent Recommendation A rare autism-associated MINT2/APBA2 mutation disrupts neurexin trafficking and synaptic function Lin AY , et al. (2019) Yes -
8 Support - Zhou X et al. (2022) Yes -
Rare Variants   (12)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain De novo - - 17989066 Kirov G , et al. (2007)
c.1015A>G p.Asn339Asp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.247G>A p.Glu83Lys missense_variant De novo - Simplex 27525107 Yuen RK et al. (2016)
c.2165A>C p.Asn722Thr missense_variant Unknown - Unknown 20029827 Babatz TD , et al. (2009)
c.11G>A p.Arg4Gln missense_variant Familial Maternal Multiplex 20029827 Babatz TD , et al. (2009)
c.410C>T p.Ala137Val missense_variant Familial Maternal Multiplex 20029827 Babatz TD , et al. (2009)
c.448C>G p.His150Asp missense_variant Familial Maternal Multiplex 20029827 Babatz TD , et al. (2009)
c.448C>G p.His150Asp missense_variant Familial Paternal Multiplex 20029827 Babatz TD , et al. (2009)
- p.Gly96_Thr98del_insAla inframe_indel Familial Paternal Multiplex 20029827 Babatz TD , et al. (2009)
c.1308G>T p.Gln436His missense_variant Familial Maternal Multiplex 20029827 Babatz TD , et al. (2009)
c.1894G>A p.Ala632Thr missense_variant Familial Maternal Multiplex 20029827 Babatz TD , et al. (2009)
c.1976C>T p.Thr659Met missense_variant Familial Paternal Multiplex 20029827 Babatz TD , et al. (2009)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

APBA2 is located within the 15q13 chromosomal region; CNVs in this region have been implicated in autism and other neurodevelopmental disorders. Babatz et al., 2009 identified seven novel nonsynonymous coding variants from a cohort of 512 ASD subjects compared to 4 such variants from a cohort of 463 controls. Functional analysis of the p.Asn723Ser missense mutation in rat Apba2 (equivalent to the ASD-associated p.Asn722Ser missense variant originally identified in Babatz et al., 2009) demonstrated that this variant resulted in reduced Nrxn1alpha membrane trafficking in transfected HEK293T cells, an increased number of immobile puncta in the Golgi appartus and neuronal processes in primary mouse neurons, altered axonal localization of Nrxn1alpha to synapses of hippocampal neurons, reduced Nrxn-mediated synapse formation, and reduced spontaneous synaptic activity at excitatory synapses (Lin et al., 2019). A de novo missense variant in the APBA2 gene was also identified in an ASD proband from a cohort of 200 Canadian ASD trio families in Yuen et al., 2016.

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

APBA2 is located within the 15q13 chromosomal region; CNVs in this region have been implicated in autism and other neurodevelopmental disorders. Babatz et al., 2009 identified seven novel nonsynonymous coding variants from a cohort of 512 ASD subjects compared to 4 such variants from a cohort of 463 controls. Functional analysis of the p.Asn723Ser missense mutation in rat Apba2 (equivalent to the ASD-associated p.Asn722Ser missense variant originally identified in Babatz et al., 2009) demonstrated that this variant resulted in reduced Nrxn1alpha membrane trafficking in transfected HEK293T cells, an increased number of immobile puncta in the Golgi appartus and neuronal processes in primary mouse neurons, altered axonal localization of Nrxn1alpha to synapses of hippocampal neurons, reduced Nrxn-mediated synapse formation, and reduced spontaneous synaptic activity at excitatory synapses (Lin et al., 2019). A de novo missense variant in the APBA2 gene was also identified in an ASD proband from a cohort of 200 Canadian ASD trio families in Yuen et al., 2016.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

APBA2 is located within the 15q13 chromosomal region; CNVs in this region have been implicated in autism and other neurodevelopmental disorders. Babatz et al., 2009 identified seven novel nonsynonymous coding variants from a cohort of 512 ASD subjects compared to 4 such variants from a cohort of 463 controls. Functional analysis of the p.Asn723Ser missense mutation in rat Apba2 (equivalent to the ASD-associated p.Asn722Ser missense variant originally identified in Babatz et al., 2009) demonstrated that this variant resulted in reduced Nrxn1alpha membrane trafficking in transfected HEK293T cells, an increased number of immobile puncta in the Golgi appartus and neuronal processes in primary mouse neurons, altered axonal localization of Nrxn1alpha to synapses of hippocampal neurons, reduced Nrxn-mediated synapse formation, and reduced spontaneous synaptic activity at excitatory synapses (Lin et al., 2019). A de novo missense variant in the APBA2 gene was also identified in an ASD proband from a cohort of 200 Canadian ASD trio families in Yuen et al., 2016.

Reports Added
[New Scoring Scheme]
4/1/2019
4
icon
4

Decreased from 4 to 4

Description

Located in 15q13 region implicated by CNVs in autism

Reports Added
[A rare autism-associated MINT2/APBA2 mutation disrupts neurexin trafficking and synaptic function.2019]
7/1/2016
4
icon
4

Decreased from 4 to 4

Description

Located in 15q13 region implicated by CNVs in autism

Reports Added
[Genome-wide characteristics of de novo mutations in autism2016]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

Located in 15q13 region implicated by CNVs in autism

4/1/2014
No data
icon
4

Increased from No data to 4

Description

Located in 15q13 region implicated by CNVs in autism

Krishnan Probability Score

Score 0.60838887218549

Ranking 283/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.073526972165298

Ranking 8160/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.83564993472169

Ranking 3005/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 9

Ranking 195/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score -0.002918038187324

Ranking 8792/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
AAGAB alpha- and gamma-adaptin binding protein Human Protein Binding 79719 Q6PD74
APBA1 Amyloid beta A4 precursor protein-binding family A member 1 Human Protein Binding 320 Q02410
APEX2 APEX nuclease (apurinic/apyrimidinic endonuclease) 2 Human Protein Binding 27301 B7ZA71
APP amyloid beta (A4) precursor protein Human Protein Binding 351 P05067
BTRC beta-transducin repeat containing E3 ubiquitin protein ligase Human Protein Binding 8945 B2R8L3
CLSTN1 calsyntenin 1 Human Protein Binding 22883 O94985
CLSTN3 calsyntenin 3 Human Protein Binding 9746 Q9BQT9
DDX24 DEAD (Asp-Glu-Ala-Asp) box polypeptide 24 Human Protein Binding 57062 Q9GZR7
DMWD dystrophia myotonica, WD repeat containing Human Protein Binding 1762 Q09019
FBXW11 F-box and WD repeat domain containing 11 Human Protein Binding 23291 Q9UKB1
HERC2 HECT and RLD domain containing E3 ubiquitin protein ligase 2 Human Protein Binding 8924 A8KAQ8
IQSEC1 IQ motif and Sec7 domain 1 Human Protein Binding 9922 B4DGC5
IQSEC2 Human Protein Binding
KLRG2 Killer cell lectin-like receptor subfamily G member 2 Human Protein Binding 346689 A4D1S0
LRP2 Megalin; low density lipoprotein receptor-related protein 2 Mouse Protein Binding 14725 A2ARV4
NECAB3 N-terminal EF-hand calcium-binding protein 3 Human Protein Binding 63941 Q96P71
nrxn1 neurexin 1 Mouse Protein Binding 18189 Q63373
PLD1 Phospholipase D1 Human Protein Binding 5337 Q13393-2
PSEN2 presenilin 2 (Alzheimer disease 4) Human Protein Binding 5664 P49810
STXBP1 syntaxin binding protein 1 Rat Protein Binding 25558 P61765
TJAP1 tight junction associated protein 1 (peripheral) Human Protein Binding 93643 Q5JTD0
TRIM41 tripartite motif containing 41 Human Protein Binding 90933 Q8WV44
ZNF518A zinc finger protein 518A Human Protein Binding NM_014803 Q6AHZ1
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